Pharmaceutical researchers have discovered in recent years that the neurons of the brain which contain monoamines are of extreme importance in a great many physiological processes which very strongly affect many psychological and personality-affecting processes as well. In particular, serotonin (5-hydroxytryptamine; 5-HT) has been found to be a key to a very large number of processes which affect both physiological and psychological functions. Drugs which influence the function of serotonin in the brain are accordingly of great importance and are now used for a surprisingly large number of different therapies.
The early generations of serotonin-affecting drugs tended to have a variety of different physiological functions, considered from both the mechanistic and therapeutic points of view. For example, many of the tricyclic antidepressant drugs are now known to be active as inhibitors of serotonin and norepinephrine reuptake, and also to have anticholinergic, antihistaminic or anti-a-adrenergic activity. More recently, it has become possible to study the function of drugs at individual receptors in vitro or ex vivo, and it has also been realized that therapeutic agents free of extraneous mechanisms of action are advantageous to the patient. Accordingly, the objective of research now is to discover agents which affect only functions of serotonin.
The present invention provides compounds which have selective activity as antagonists and partial agonists of the serotonin-1A receptor and the serotonin-2A receptor, and activity as inhibitors of serotonin reuptake. The best-known pharmaceutical with the latter efficacy is fluoxetine, and the importance of its use in the treatment of depression and other conditions is extremely well documented and publicized. Recent scientific articles, for example, Artigas, TIPS, 14, 262 (1993), have suggested that the efficacy of a reuptake inhibitor may be decreased by the activation of serotonin-1A receptors with the resultant reduction in the firing rate of serotonin neurons. Accordingly, present research in the central nervous system is focusing on the effect of combining reuptake inhibitors with compounds which affect the 5-HT1A receptor. In addition, it has been suggested that a 5-HT2A receptor antagonist would provide treatment of depression with fewer side effects than a typical serotonin reuptake inhibitor.
Compounds exhibiting both serotonin reuptake inhibition activity and 5-HT1A antagonist activity have been described, for example in U.S. Pat. No. 5,576,321, issued Nov. 19, 1996. It has been found that the compounds of the present invention are potent serotonin reuptake inhibitors, antagonists of the 5-HT1A receptor and antagonists of the 5-HT2A receptor.
The present invention provides compounds of formula I: 
wherein:
X is O, S, NR, S(xe2x95x90O), or S(xe2x95x90O)2;
Y is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90NOR), CHNR7R, S, SO, or SO2;
------- represents a single or a double bond;
n is 1, 2, 3 or 4;
R is H or C1-C6 alkyl;
R1a, R1b, R1c and R2 are each independently H, F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, xe2x80x94NR7R8, xe2x80x94C(xe2x95x90O)NR7R8, xe2x80x94NR7C(xe2x95x90O)R8, CN or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN;
R3 is H, OH, hydroxy(C1-C6)alkyl, C1-C6 alkyl, C1-C6 alkoxy, or (C1-C6)alkylthio;
R4 is aryl, heterocycle, C3-C8 cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN; or heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN;
R5 is aryl, heterocycle, C3-C8 cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN; or heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN;
R6a and R6b are each independently H or C1-C3 alkyl;
R7 and R8 are each independently H, C1-C6 alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN;
and the pharmaceutically acceptable salts thereof.
The present invention further provides a method of inhibiting the reuptake of serotonin and antagonizing the 5-HT1A receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.
In addition, the present invention provides a method of inhibiting the reuptake of serotonin, antagonizing the 5-HT1A receptor, and antagonizing the 5-HT2A receptor, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.
More particularly, the present invention provides a method for alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine; a method of treating anxiety; and a method of treating a condition chosen from the group consisting of depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine; which methods comprise administering to a subject in need of such treatment an effective amount of a compound of formula I.
In addition, the present invention provides a method of potentiating the action of a serotonin reuptake inhibitor comprising administering to a subject in need of such treatment a compound of formula I in combination with a serotonin reuptake inhibitor.
In addition, the invention provides pharmaceutical compositions of compounds of formula I, including the hydrates thereof, comprising, as an active ingredient, a compound of formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of formula I.
The invention further provides intermediates of the formula: 
wherein:
X is O, S, NR, S(xe2x95x90O), or S(xe2x95x90O)2;
------- represents a single or a double bond;
R is H or C1-C6 alkyl;
R1a, R1b, R1c and R2 are each independently H, F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, xe2x80x94NR7R8, xe2x80x94C(xe2x95x90O)NR7R8, xe2x80x94NR7C(xe2x95x90O)R8, CN or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN;
R6a, and R6b are each independently H or C1-C3 alkyl;
R7 and R8 are each independently H, C1-C6 alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN.
In addition, the invention further provides intermediates of the formula: 
wherein:
X is O, S, NR, S(xe2x95x90O), or S(xe2x95x90O)2;
------- represents a single or a double bond;
R is H or C1-C6 alkyl;
R1a, R1b, R1c and R2 are each independently H, F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, xe2x80x94NR7R8, xe2x80x94C(xe2x95x90O)NR7R8, xe2x80x94NR7C(xe2x95x90O)R8, CN or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN;
R6a and R6b are each independently H or C1-C3 alkyl;
R7 and R8 are each independently H, C1-C6 alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, phenyl, NO2, NH2, or CN.
According to another aspect, the present invention provides the use of a compound of formula I for the manufacture of a medicament for inhibiting the reuptake of serotonin, antagonizing the 5-HT1A receptor, and antagonizing the 5-HT2A receptor.
In addition, the present invention provides the use of a compound of formula I for inhibiting the reuptake of serotonin, antagonizing the 5-HT1A receptor, and antagonizing the 5-HT2A receptor.
As used herein, an acyclic or cyclic acetal or ketal is represented by the following: 
and corresponds for example, to the following groups: 
As used herein the term xe2x80x9cPgxe2x80x9d refers to a protecting group on the amine which are commonly employed to block or protect the amine while reacting other functional groups on the compound. Examples of protecting groups (Pg) used to protect the amino group and their preparation are disclosed by T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d John Wiley and Sons, 1981, pages 218-287. Choice of the protecting group used will depend upon the substituent to be protected and the conditions that will be employed in subsequent reaction steps wherein protection is required, and is well within the knowledge of one of ordinary skill in the art. Preferred protecting groups are t-butoxycarbonyl also known as a BOC protecting group, and benzyloxycarbonyl.
As used herein, the terms xe2x80x9cHaloxe2x80x9d, xe2x80x9cHalidexe2x80x9d or xe2x80x9cHalxe2x80x9d refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
As used herein, the term xe2x80x9cMexe2x80x9d refers to a methyl group, the term xe2x80x9cEtxe2x80x9d refers to an ethyl group, the term xe2x80x9cPrxe2x80x9d refers to a propyl group, the term xe2x80x9ciPrxe2x80x9d refers to an isopropyl group, xe2x80x9cBuxe2x80x9d refers to a butyl group, and the term xe2x80x9cPhxe2x80x9d refers to a phenyl group.
As used herein the term xe2x80x9cserotoninxe2x80x9d is equivalent to and interchangeable with the terms xe2x80x9c5-HTxe2x80x9d or xe2x80x9c5-hydroxytryptaminexe2x80x9d.
As used herein the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes within its definition the term xe2x80x9cC1-C4 alkylxe2x80x9d.
As used herein the term xe2x80x9chalo(C1-C6)alkylxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(C1-C6)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like. The term xe2x80x9chalo(C1-C6)alkylxe2x80x9d includes within its definition the term xe2x80x9chalo(C1-C4)alkylxe2x80x9d.
As used herein the term xe2x80x9chydroxy(C1-C6)alkylxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms with a hydroxy group attached to it, such as xe2x80x94CH2OH, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2CH2OH, and the like. The term xe2x80x9chydroxy(C1-C6)alkylxe2x80x9d includes within its definition the term xe2x80x9chydroxy(C1-C4)alkylxe2x80x9d.
As used herein the term xe2x80x9c(C1-C6)alkylthioxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom. Typical (C1-C6)alkylthio groups include xe2x80x94SCH3, xe2x80x94SCH2CH3, xe2x80x94S(CH2)2CH3, xe2x80x94S(CH2)3CH3, xe2x80x94S(CH2)4CH3, xe2x80x94S(CH2)5CH3, and the like. The term xe2x80x9c(C1-C6)alkylthioxe2x80x9d includes within its definition the term xe2x80x9c(C1-C4)alkylthioxe2x80x9d.
As used herein the term xe2x80x9cC1-C6 alkoxyxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C1-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term xe2x80x9cC1-C6 alkoxyxe2x80x9d includes within its definition the term xe2x80x9cC1-C4 alkoxyxe2x80x9d.
As used herein the term xe2x80x9chydroxy(C1-C6)alkylxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms with a hydroxy group attached to it. Typical hydroxy(C1-C6)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyisopropyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxyisobutyl, hydroxy-t-butyl, 1-hydroxypentyl, 1-hydroxyhexyl and the like. The term xe2x80x9chydroxy(C1-C6)alkylxe2x80x9d includes within its definition the term xe2x80x9chydroxy(C1-C4)alkylxe2x80x9d.
As used herein the term xe2x80x9cC3-C8 cycloalkylxe2x80x9d refers to a saturated hydrocarbon ring structure containing from three to eight carbon atoms. Typical C3-C8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
As used herein the term xe2x80x9carylxe2x80x9d refers to a phenyl or naphthyl group.
As used herein the term xe2x80x9cheterocyclexe2x80x9d refers to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated or unsaturated, and consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure.
Examples of such heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl-sulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.
As used herein, the following numbering system applies to the bicyclic portion of formula I as follows: 
In addition, it is appreciated by one of ordinary skill in the art that formula I encompasses the following structures: 
This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I. A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as xe2x80x9cepimersxe2x80x9d. The terms xe2x80x9cracematexe2x80x9d, xe2x80x9cracemic mixturexe2x80x9d or xe2x80x9cracemic modificationxe2x80x9d refer to a mixture of equal parts of enantiomers.
The term xe2x80x9cenantiomeric enrichmentxe2x80x9d as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or xe2x80x9ceexe2x80x9d, which is found using the following equation:   ee  =                              E          1                -                  E          2                                      E          1                +                  E          2                      xc3x97    100  
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formulas I or Ia can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981. Examples of resolutions include recrystallization techniques or chiral chromatography.
Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoismeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in xe2x80x9cNomenclature of Organic Compounds: Principles and Practicexe2x80x9d, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
As used herein, the term xe2x80x9cSRIxe2x80x9d refers to serotonin reuptake inhibitor.
The compounds of formula I can be prepared by techniques and procedures readily available to one of ordinary skill in the art, for example by following the procedures as set forth in the following Schemes. These schemes are not intended to limit the scope of the invention in any way. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. Scheme I provides a synthesis of compounds of structure (8). 
In Scheme I, step A, the compound of structure (1) is alkylated with a compound of structure (2) under conditions well known in the art. For example, compound (1) is dissolved in a suitable organic solvent, such as dimethylformamide (DMF) or tetrahydrofuran (THF). Examples of compound (1) include 2-bromothiophenol, 2-bromophenol, 2-bromo-3-fluorophenol, 2-bromo-4-fluorophenol, 2-bromo-5-fluorophenol, 2-chloro-4-(1,1-dimethylethyl)phenol, 2-bromo-5-chlorophenol, 3-bromo-4-hydroxybenzonitrile, 2-chloro-4-(tert-phenyl)phenol, 2-chloro-5-(trifluoromethyl)phenol, 3-chloro-4-hydroxy-benzotrifluoride, 2-chloro-4-nitrophenol, 3-chloro-4-biphenylol, 3-bromo-4-hydroxybiphenyl, 2-chloro-4-fluorothiophenol, 2-chloro-4-methylphenol, 2-chloro-4-methoxyphenyl, 2-chloro-5-methoxyphenol, 2-bromo-4-methylphenol, 2-chloro-5-methylphenol, 4-bromoresorcinol, 4-chlororesorcinol, 2-bromo-4-chlorophenol, and the like. As used in Scheme I, Hal represents Cl, Br or I only, and X represents S, O or NR. The solution is treated with a slight excess of a suitable base, such as potassium carbonate or sodium hydride followed by addition of about 1.05 to about 1.20 equivalents of compound (2). Examples of compound (2) include bromoacetaldehyde diethyl acetal, 2-bromomethyl-1,3-dioxolane and the like. The reaction mixture is then stirred at room temperature to reflux for about 1 to 7 hours. The product is then isolated and purified by extraction techniques and chromatography. For example, the reaction is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is then purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide compound (3).
In Scheme I, step B, compound (3) is cyclized to the compound of structure (4) under acidic conditions. For example, compound (3) is dissolved in a suitable organic solvent, such as chlorobenzene and the solution is added dropwise to a refluxing mixture of polyphosphoric acid and chlorobenzene. The reaction mixture is heated at reflux for about 2 to 5 hours and then cooled to room temperature. The compound (4) is then isolated and purified by techniques well known in the art. For example, the reaction mixture is made slightly basic with 1N sodium hydroxide and then extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is then purified by flash chromatography on silica gel with a suitable eluent, such as hexane or ethyl acetate/hexane to provide the compound (4).
In Scheme I, step C, compound (4) undergoes an aldol reaction with the piperidone of structure (5) under standard conditions well known in the art, such as Grignard Type conditions (See for example J. March, xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure,xe2x80x9d 2nd Edition, McGraw-Hill, 1977, 836-841), to provide the alcohol of structure (6). For example, compound (4) is dissolved in a suitable organic solvent, such as diethyl ether and the solution is added dropwise to a mixture of about 2 equivalents of magnesium suspended in diethyl ether. If necessary, about 1 equivalent of dibromoethane is then added and the reaction is heated to reflux for about 1 to 5 hours. The reaction is then cooled to room temperature and about 1 equivalent of the piperidone (5) is added to the prepared Grignard reagent. The reaction is then allowed to stir at room temperature for about 5 to 18 hours. The reaction is quenched by addition of water and the alcohol (6) is isolated and purified by techniques well known in the art. For example, the quenched reaction is extracted with a suitable organic solvent, such as diethyl ether, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is then purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide alcohol (6).
In Scheme I, step D, alcohol (6) is deprotected and dehydrated under standard conditions well known in the art to provide to provide the 1,2,3,6-tetrahydropyridine of structure (7). One of ordinary skill in the art would readily appreciate that deprotection and dehydration can be carried out in a stepwise fashion, in any order, or concomitantly. For example, step D is carried out concomitantly by dissolving the alcohol (6) in a suitable organic solvent, such as toluene and treating the solution with an excess of a suitable acid, such as p-toluenesulfonic acid. The reaction is heated at reflux for about 1 to 4 hours, then cooled and the solution is made basic with a suitable base, such as 1N sodium hydroxide. The 1,2,3,6-tetrahydropyridine (7) is then isolated and purified by techniques well known in the art. For example, the solution is extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue can then be purified if necessary by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide 1,2,3,6-tetrahydropyridine (7).
In Scheme I, step E, 1,2,3,6-tetrahydropyridine (7) can be hydrogenated under conditions well known in the art to provide the piperidine of structure (8). For example, the 1,2,3,6-tetrahydropyridine (7) is dissolved in a suitable organic solvent, such as absolute ethanol, and treated with a suitable hydrogenation catalyst, such as 10% palladium on carbon. The reaction mixture is then treated with an excess of ammonium formate and the reaction is heated at reflux for about 2 to 4 hours. The reaction mixture is then cooled, filtered to remove the catalyst and the filtrate is concentrated under vacuum to provide piperidine (8). The piperidine (8) can be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane. Alternatively, the residue can be converted to a pharmaceutically acceptable salt, such as the oxalate salt by dissolving the residue in methanol, treating with 1 equivalent of oxalic acid and then concentrating the solution under vacuum. The solid can then be purified by recrystallization from a suitable organic solvent, such as diethyl ether to provide the purified oxalate salt of piperidine (8).
Scheme IA provides an alternative synthesis for the preparation of compound (4). 
In Scheme IA, step A, compound (1) is alkylated with a compound of structure (9) in a manner analogous to the procedure described above in Scheme I, step A to provide the alkylated compound of structure (10). As used in Scheme IA, Hal represents Cl, Br or I only, and X represents S, O or NR. For example, compound (1) is dissolved in a suitable organic solvent, such as tetrahydrofuran and a slight excess of a suitable base, such as potassium carbonate. The mixture is then treated with about 1.05 to 1.2 equivalents of compound (9), such as ethyl 2-bromopropionate, and a catalytic amount of potassium iodide, and the reaction is heated at reflux for about 2 to 5 hours. The reaction is then cooled, diluted with water and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide alkylated compound (10).
In Scheme IA, step B, alkylated compound (10) is reduced to the aldehyde of structure (11) under conditions well known in the art. For example, the alkylated compound (10) is dissolved in a suitable organic solvent, such as toluene and cooled to about xe2x88x9278xc2x0 C. The cooled solution is then treated dropwise with about 1.00 -1.05 equivalents of a suitable reducing agent, such as diisobutylaluminum hydride in toluene. The reaction is then stirred for about 20 to 60 minutes at xe2x88x9278xc2x0 C. and then quenched with methanol. After warming to room temperature, the reaction is treated with saturated sodium tartrate solution and stirred for about 30 minutes. The mixture is then extracted with a suitable organic solvent, such ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide aldehyde (11).
In Scheme IA, step C the aldehyde (11) is cyclized to the compound of structure (4) in a manner analogous to the procedure described above in Scheme I, step B.
Scheme II provides an alternative synthesis of compound (7). 
In Scheme II, step A, protected piperidone (5) is converted to the tin derivative (12) under conditions well known in the art. For example, diisopropylamine is dissolved in a suitable organic solvent, such as tetrahydrofuran and the solution is cooled to about 0xc2x0 C. An equivalent of n-butyllithium is added and the reaction is stirred for about 15 minutes to one hour. Then one equivalent of tri-n-butyltinhydride is added dropwise to the solution, the reaction mixture is stirred for about one hour and then cooled to about xe2x88x9278xc2x0 C. To this reaction mixture is added dropwise about 0.85 equivalents of the protected piperidone (5) dissolved in tetrahydrofuran. The reaction is then stirred for about 1 to 5 hours at xe2x88x9278xc2x0 C. and then quenched with buffer (pH 6). The reaction mixture is extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the tin derivative (12).
In Scheme II, step B, tin derivative (12) is dehydrated to the 1,2,3,6-tetrahydropyridine (13) under standard conditions. For example, the tin derivative (12) is dissolved in a suitable organic solvent, such as methylene chloride and the solution is cooled to about 0xc2x0 C. An excess of triethylamine and about 2.0 equivalents of methanesulfonyl chloride are added to the solution which is allowed to stir for about 4 to 20 hours. The reaction mixture is warmed to room temperature and concentrated under vacuum. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the 1,2,3,6-tetrahydropyridine (13).
In Scheme II, step C the 1,2,3,6-tetrahydropyridine (13) is coupled with compound (4), prepared in Scheme I, to provide the compound of structure (14). For example, one equivalent of compound (4) and one equivalent of 1,2,3,6-tetrahydropyridine (13) are combined in a suitable organic solvent, such as toluene. A catalytic amount of 2,6-di-tert-butyl-4-methylphenol and a catalytic amount of tetrakis(triphenylphosphine)palladium(0) are added and the reaction mixture is heated at reflux for about 15 to 20 hours. The reaction mixture is then cooled, concentrated under vacuum and the residue purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide compound (14).
In Scheme II, step D, compound (14) is deprotected under conditions well known in the art to provide the compound of structure (7). For example, compound (14) is dissolved in a suitable organic solvent, such as toluene and treated with a suitable acid, such a p-toluenesulfonic acid. The reaction is heated at reflux for about 1 to 2 hours, then cooled to room temperature. The mixture is diluted with a suitable organic solvent, such as ethyl acetate, washed with sodium hydroxide solution, the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated to provide compound (7).
Scheme III provides a synthesis of the aldehydes of structure (20). 
In Scheme III, step A, the compound of structure (15) is alkylated with the compound of structure (16) to provide the compound of structure (17) under conditions well known in the art. When G is hydrogen and R4 is 2-pyridyl, 3-pyridyl or 4-pyridyl, for example, then a base, such as n-butyllithium is used to prepare the corresponding anion which is reacted with compound (16). For example, compound (15) is dissolved in a suitable organic solvent, such as tetrahydrofuran and cooled to about xe2x88x9278xc2x0 C. About 1.1 equivalents of n-buytllithium is added to the cooled solution which is then allowed to warm to room temperature over one hour. The solution is then re-cooled to about xe2x88x9278xc2x0 C. and treated dropwise with about 1.05 equivalents of a compound of structure (16) dissolved in tetrahydrofuran. [Compounds of structure 16 are readily prepared by one of ordinary skill in the art following generally the procedure disclosed by Brornidge, S. M., et al., Synthetic Communications, 23(4), 487-494 (1993).] The reaction is then allowed to warm to room temperature and stirred for about 20 to 40 hours. The reaction mixture is then diluted with water and dilute acid maintaining a pH of about 12. The quenched reaction is then extracted with a suitable organic solvent, such as methylene chloride, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is then purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the compound (17).
Alternatively, when G is Cl or Br and R4 is aryl, for example, a Grignard reagent is prepared, using techniques and procedures well known in the art, from magnesium in a suitable organic solvent, such as diethyl ether or tetrahydrofuran and refluxing as necessary. The resulting Grignard reagent is then combined with the compound (16) to provide compound (17).
In Scheme III, step B, compound (17) is alkylated with a compound of structure (18) to provide the compound of structure (19) under conditions well known in the art. For purposes of Scheme III, Hal represents Cl, Br or I. For example, compound (17) is dissolved in a suitable organic solvent and treated with a suitable base. Examples of suitable organic solvents are tetrahydrofuran, methyl sulfoxide, dimethylformamide, methyl sulfoxide/tetrahydrofuran, dimethylformamide/tetrahydrofuran, and the like. Examples of suitable bases are potassium tert-butoxide, n-butyllithium, sodium hydride, and the like. For example, compound (17) is dissolved in tetrahydrofuran, and the solution is added dropwise to a cooled suspension (0xc2x0 C.) of 1.4 equivalents of sodium hydride in tetrahydrofuran. The reaction is warmed to room temperature and stirred for about 2 to 4 hours. Then about 1.5 equivalents of a compound (18) is added to the reaction which is then heated at reflux for about 16 hours. The reaction is then diluted with water, extracted with a suitable eluent, such as diethyl ether, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide compound (19).
In Scheme III, step C, compound (19) is hydrolyzed under conditions well known in the art to provide the aldehyde of structure (20). For example, compound (19) is dissolved in a suitable organic solvent, such as acetone and treated with an excess of a suitable acid, such as 3N HCl. The reaction is stirred at room temperature for about 10 to 20 hours. It is then neutralized with a suitable base, such as 1 N sodium hydroxide. The neutralized mixture is then extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the aldehyde (20).
Scheme IV provides a synthesis of compounds of formulas Ia through Id. All substituents, unless otherwise specified, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. 
In Scheme IV, step A, compounds (7) or (8), prepared in Scheme I above, are subjected to a reductive alkylation with compound (20), prepared in Scheme III above, under conditions well known in the art, such as those disclosed in J. March, xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms and Structurexe2x80x9d, 2nd Edition, McGraw-Hill, 1978, 819-820, to provide the compound of formula (Ia). For example, in Scheme IV, step A, about one equivalent of either compound (7) or (8) is combined with one equivalent of compound (20) in a suitable organic solvent, such as methylene chloride. To this solution is added about 2.5 equivalents of acetic acid and about 1.3 equivalents of sodium triacetoxyborohydride. The reaction is stirred at room temperature for about 4 to 24 hours and then made basic with 1N sodium hydroxide. The mixture is then extracted with a suitable organic solvent, such as methylene chloride, the combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude compound of formula Ia. This material can be purified by techniques well known in the art. For example, the crude material is purified by flash chromatography on silica gel with a suitable eluent such as ethyl acetate/hexane. The purified compound of formula Ia can then be converted to the pharmaceutically acceptable salt, such as the oxalate salt by dissolving in methanol and treating with one equivalent of oxalic acid. The solvent is then removed under vacuum to provide the oxalate salt of formula Ia. The oxalate salt can be further purified by recrystallization from suitable organic solvents, such as methylene chloride and hexane.
Alternatively, the crude compound of formula Ia can be purified by direct conversion of the crude free base to the pharmaceutically acceptable salt, such as the oxalate salt, and recrystallized from a suitable organic solvent, such as methylene chloride and hexane.
In Scheme IV, step B, formula Ia is hydrogenated under conditions well known in the art to provide the compound of formula Ib. For example, compound of formula Ia is dissolved in absolute ethanol and treated with 10% palladium on carbon. The reaction is stirred under an atmosphere of hydrogen for about 1 to 24 hours. The reaction is then filtered to remove the catalyst and the filtrate is concentrated under vacuum. The residue is purified by techniques well known in the art, such as those described in step A above to provide the compound of formula Ib as either the free base or a pharmaceutically acceptable salt.
In Scheme IV, step D, formula Ib is further reduced under conditions well known in the art to provide the compound of formula Ic. For example, the compound of formula Ib is dissolved in a suitable organic solvent such as methylene chloride, cooled to about xe2x88x9278xc2x0 C. and treated with a suitable reducing agent, such as about 3 equivalents of diisobutylaluminum hydride or lithium aluminum hydride. The reaction is then slowly warmed to room temperature over about 2 hours and then stirred at room temperature for about 16 hours. The reaction is then diluted with saturated aqueous potassium sodium tartrate solution and extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the free base of the compound of formula Ic. As described above in step A, this free base can then be converted to the pharmaceutically acceptable salt, such as an oxalate salt.
In Scheme IV, step C the compound of formula Ia is reduced to the compound of formula Id in a manner analogous to the procedure described above in step D. In addition, the free base of formula Id is converted to the pharmaceutically acceptable salt in a manner analogous to the procedure described in step A above.
Scheme V provides a synthesis of the compound of formula Ie. Reagents and starting materials are readily available to one of ordinary skill in the art. All substituents are previously defined, unless otherwise indicated. 
In Scheme V, step A, a compound of structure (21) is alkylated with a compound of structure (22) under conditions well known in the art to provide the compound of structure (23). When G is hydrogen and R4 is 2-pyridyl, 3-pyridyl or 4-pyridyl, for example, then a base, such as n-butyllithium is used to prepare the corresponding anion which is reacted with compound (22). For example, compound (21) is dissolved in a suitable organic solvent, such as THF and treated with a suitable base, such as n-butyllithium at about xe2x88x9278xc2x0 C. The mixture is warmed to room temperature and then cooled back down to xe2x88x9278xc2x0 C. and treated with about 1.05 equivalents of a compound (22), wherein for the purposes of Scheme V, Hal represents Cl, Br or I. The reaction is warmed to room temperature and allowed to stir for 10 to 20 hours. It can then be heated to reflux for about 2 to 24 hours and then cooled to room temperature. The solvent is then removed under vacuum, the residue dissolved in a suitable organic solvent, such as ethyl acetate, followed by addition of water. The layers are separated, and the aqueous is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide compound (23).
Alternatively, when G is Cl or Br and R4 is aryl, for example, a Grignard reagent is prepared, using techniques and procedures well known in the art, from magnesium in a suitable organic solvent, such as diethyl ether or tetrahydrofuran and refluxing as necessary. The resulting Grignard reagent is then combined with the compound (22) under standard conditions to provide compound (23). Additional conditions for coupling of alkyl halides with organometallic reagents, can be found in J. March, xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms and Structurexe2x80x9d, 2nd Edition, McGraw-Hill, 1978, pages 409-412.
In Scheme V, step B, compound (23) is alkylated with compound (18) in a manner analogous to the procedure described in Scheme III, step B to provide the compound of structure (24). As used herein, Hal represents Cl, Br or I only.
In Scheme V, step C, compound (24) is hydrolyzed under acidic conditions in a manner analogous to the procedure described in Scheme III, step C to provide the aldehyde of structure (25).
In Scheme V, step D, compound (25) is used to reductively alkylate with compound (7) [prepared in Scheme I or II above] or compound (8) [prepared in Scheme I above], in a manner analogous to the procedure described in Scheme IV, step A to provide the compound of formula Ie.
Compounds wherein X is S(xe2x95x90O) or S(xe2x95x90O)2 in formula I are readily prepared by one of ordinary skill in the art using well known techniques and procedures. For example, compounds of formulas Ia-Ie wherein X is S can be oxidized under standard conditions, such as treatment with m-chloroperbenzoic acid, to provide the corresponding sulfone [S(xe2x95x90O)2] or sulfoxide [S(xe2x95x90O)].
Intermediate aldehyde of structure (20a) can be prepared as described in Scheme VI below. Aldehyde (20a) is reductively aminated in a manner analogous to aldehyde (20) to provide compound of formula I. The reagents and starting materials are readily available to one of ordinary skill in the art. 
In Scheme VI, step A, aldehyde (26) is combined with a suitable organometallic reagent (27) under conditions well known in the art to provide alcohol (28). Examples of suitable organometallic reagents include Grignard Reagents, alkyl lithium reagents, and the like. Grignard Reagents are preferred. For examples of typical Grignard Reagents and reaction conditions, see J. March, xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 2nd Edition, McGraw-Hill, pages 836-841 (1977). More specifically, aldehyde (26) is dissolved in a suitable organic solvent, such as tetrahydrofuran, cooled to about xe2x88x925xc2x0 C. and treated with about 1.1 to 1.2 equivalents of a Grignard reagent of formula (27) wherein M is MgCl or MgBr. The reaction is allowed to stir for about 1 to 2 hours, then quenched, and alcohol (28) is isolated. For example, the reaction mixture is poured onto ice-cold 1N HCl, the quenched mixture is extracted with a suitable organic solvent, such as toluene, the organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide alcohol (28).
In Scheme VI, step B, alcohol (28) is oxidized under standard conditions well know in the art, such as those described by J. March, xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 2nd Edition, McGraw-Hill, pages 1082-1084 (1977), to provide ketone (29).
For example, alcohol (28) is dissolved in a suitable organic solvent, such as methylene chloride, the solution cooled with a wet ice-acetone bath, and treated with 2.5 to 3.0 equivalents of dimethyl sulfoxide. After stirring for about 30 minutes, the reaction is then treated with about 1.8 equivalents of P2O5. The reaction is allowed to stir for about 3 hours and then is treated over about 30 minutes with about 3.5 equivalents of a suitable amine, such as triethylamine. The cooling bath is then removed and the reaction is allowed to stir for about 8 to 16 hours. The ketone (29) is then isolated by standard extraction techniques well known in the art.
In Scheme VI, step C, ketone (29) is treated with a suitable base followed by addition of the alkene (30), wherein X is a suitable leaving group, to provide compound (31). For example, ketone (29) is combined with an excess of alkene (30) in a suitable organic solvent, such as tetrahydrofuran, and cooled with a wet ice acetone bath. Examples of suitable leaving groups are Cl, Br, I, and the like. Preferred leaving groups are Cl and Br. About 1.1 equivalents of a suitable base, such as potassium tert-butoxide, is added and the reaction is allowed to stir for about 2 hours at room temperature. The reaction is then quenched with aqueous acid and compound (31) is isolated by extraction with heptane. The heptane extracts are washed with sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide compound (31).
In Scheme VI, step D, compound (31) is treated with a suitable oxidizing agent to provide aldehyde (20a). Ozone is the preferred oxidizing agent. Examples of suitable oxidizing reagents and conditions are described by J. March, xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 2nd Edition, McGraw-Hill, pages 1090-1096 (1977).
For example, compound (31) is dissolved in a suitable organic solvent, such as methanol, a small amount of Sudan III is added, and the solution is cooled to about xe2x88x9220xc2x0 C. Ozone is bubbled into the solution for about 4 hours until the pink color turns to a pale yellow color. Then Me2S is added to the reaction mixture and the cooling bath is removed. Concentration of the reaction mixture under vacuum provides the intermediate dimethyl acetal of aldehyde (20a). This dimethyl acetal is readily hydrolyzed under standard acidic conditions to provide aldehyde (20a). Alternatively, direct acidic work-up of the crude reaction mixture provides aldehyde (20a).
The compounds of formulas If, Ig, Ih and Ij can be prepared as described in Scheme VII. The reagents and starting materials are readily available to one of ordinary skill in the art. Unless otherwise specified, the substituents are as previously defined. 
In Scheme VII, step A, the compounds of formula Ia or formula Ib are converted to the corresponding oxime of formulas If and Ig under conditions well known in the art. For example, the compounds of formula Ia or Ib are dissolved in a suitable solvent or solvent mixture, such as ethanol/water and treated with an excess of a suitable hydroxylamine, such as hydroxylamine hydrochloride. The reaction mixture is heated at reflux for 16 to 24 hours and then the compounds of formulas If and Ig are isolated and purified using standard techniques and procedures, such as extraction techniques and flash chromatography. For example, the cooled reaction is diluted with a suitable organic solvent, such as ethyl acetate, the organic layer is separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude oximes. The crude material can then be purified by flash chromatography on silica gel with a suitable eluent, such as methanol/ethyl acetate to provide the purified compounds of formulas If and Ig.
In Scheme VII, step B compounds of formulas If and Ig are reduced under standard conditions to provide the amines of formulas Ih and Ij. For example, the compounds of formula If or Ig are dissolved in a suitable organic solvent, such as diethyl ether and treated with a suitable reducing agent, such as lithium aluminum hydride. The reaction is stirred at a temperature of about room temperature to reflux for about 3 to 24 hours. The reaction is then quenched with 1N sodium hydroxide and the desired compounds of formulas Ih and Ij are isolated and purifed using standard techniques and procedures. For example, the quenched reaction mixture is extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude material. The crude material is then purified by flash chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride with ammonia added to provide the purified compounds of formulas Ih and Ij. The free bases are converted to the corresponding pharmaceutically acceptable salts using standard procedures well known to one of ordinary skill in the art.